Novel 3D images of the structural biology of the insulin receptor will pave the way for better insulin analogue design, Australian researchers say.
An international collaboration co-led by researchers at the Walter and Eliza Hall Institute in Melbourne has used electron microscopy mappings to elucidate the structure of insulin molecule binding to a receptor.
Published in Nature Communications, the study reveals the first definitive 3D image of how insulin successfully interacts with its receptor and the signalling process to lower glucose levels.
“This image could be a game-changer for designing faster-acting and longer-lasting insulin therapies,” say the researchers, co-led by Associate Professor Mike Lawrence from the Walter and Eliza Hall Institute, in collaboration with teams at the European Molecular Biology Laboratory (EMBL) and from the pharmaceutical company Sanofi-Aventis in Germany.
Associate Professor Lawrence said it is well established that insulin instructs cells to lower blood glucose levels by binding to a receptor on the cell surface, but the problem was that no one knows precisely what is occurring during the interaction.
“Current insulin therapies are sub-optimal because they have been designed without this missing piece of the puzzle,” he said.
“Together with our collaborators in Germany, we have produced the first definitive 3D image of the way in which insulin binds to the surface of cells in order to successfully transmit the vital instructions needed for taking up sugar from the blood.”
The structure reveals how the membrane proximal domains of the receptor come together to effect signalling and how insulin’s negative cooperativity of binding arises.
Associate Professor Lawrence said the detailed image was the outcome of a collaboration between structural and cell biology experts from the Institute, working together with both cryo-electron microscopy specialists at EMBL in Heidelberg and an insulin receptor specialist from the University of Chicago.
“We knew that insulin underwent a physical change that signalled its successful connection with its receptor on the cell surface. But we had never before seen the detailed changes that occurred in the receptor itself, confirming that insulin had successfully delivered the message for the cell to take up sugar from the blood.
“My colleagues at the Institute carefully engineered individual samples of insulin bound to receptors so that our collaborators in Heidelberg could use cryo-electron microscopy to capture hundreds of thousands of high-resolution ‘snap shots’ of these samples.
“We then combined more than 700,000 of these 2D images into a high-resolution 3D image showing precisely what the successful binding between insulin and its receptor looks like. And there it was before our eyes, the full picture in exquisite detail.
“It was at that point we knew we had the information needed to develop improved insulin therapies that could ensure cells would respond correctly and carry out the functions necessary to lower blood sugar levels,” Associate Professor Lawrence said.
Associate Professor Lawrence said the findings meant it would now be possible to design insulin therapies that could mimic more closely the body’s own insulin.
“Going forward, pharmaceutical companies will be able to use our data as a ‘blueprint’ for designing therapies that optimise the body’s uptake of insulin. There has already been great interest in these results and their application, and the Institute has a network of collaborations underway.
“After more than two decades of research by Melbourne scientists to get to this point, it is phenomenal to have achieved results that will ultimately benefit patients with the development of more effective therapies, particularly for those whose lives are dependent on a daily injection of insulin,” he said.